S-adenosylmethionine (SAMe) is an important methyl donor and antioxidant. Depressed SAMe levels are observed in multiple forms of experimental liver injury, and SAMe therapy is an effective hepatoprotective agent in diverse forms of experimental liver injury. SAMe is available as a complementary and alternative medicine and is widely used to treat several forms of liver disease as well as depression. Likely therapeutic properties of SAMe include its effects on methylation, antioxidant status, mitochondrial function, hepatocyte differentiation, cytokine metabolism, and/or antidepressive functions. In this proposal, we will evaluate potential benefits of SAMe in an emerging major health problem in the U.S., non-alcoholic steatohepatitis (NASH). While the etiology of NASH still remains unclear, most investigators agree that a baseline of steatosis requires a second "hit" capable of inducing inflammation, fibrosis or necrosis in order to develop NASH. The focus of our research group has been the interactions of cytokines, oxidative stress with lipid peroxidation, and mitochondrial dysfunction in the induction of steatohepatitis, both alcoholic and nonalcoholic in origin. Recent research from other laboratories also supports increased cytokine activity, oxidative stress, and mitochondrial dysfunction in the pathogenesis of NASH. Our long-term goal is to further understand mechanism(s) of action of SAMe in liver disease. In this proposal we will evaluate specific mechanisms of action of SAMe in the human liver disease NASH. This is not a clinical trial, but a mechanistic translational study. The specific objectives for this proposal are: 1 .Evaluate mechanisms for dysregulated TNF/cytokine production in patients with NASH and determine whether or not SAMe in vitro/ex vivo favorably modulates this abnormal cytokine metabolism;2. Evaluate in vivo mechanisms of action of SAMe in NASH patients, including antioxidant status, cytokine metabolism, liver function, and quality of life issues;3. Determine whether or not hepatic methyltransferases are decreased in NASH and improve with SAMe therapy;and 4. Determine by proteomic analysis of serum and liver biopsies the proteins (esp. oxidative stress, oxidized and mitochondrial proteins) that may play a role in the diagnosis or etiology of NASH, and which may be modified by SAMe therapy